Nuclear factor-B (NF-B) promotes cell survival by upregulating expression of anti-apoptotic genes, a process that is antagonized by inhibitors of B (IB) factors1. The only NF-B family member known to be mutated in human cancer is NF-B2 p100 (ref. 2), a factor with IB activity. Here, we report the isolation from irradiated mouse tumour cells of a complex that induces caspase-8 activity in cell-free assays and identify p100 as an essential component of this complex. Expression of p100 profoundly sensitizes cells to death-receptor-mediated apoptosis through a pathway that is independent of IB-like activity. The carboxyl terminus of p100 contains a death domain3 that is absent from all known tumour-derived mutants. This death domain mediates recruitment of p100 into death machinery complexes after ligand stimulation and is essential for p100's pro-apoptotic activity. p100 also sensitizes NIH3T3 cells to apoptosis triggered by oncogenic Ras, resulting in a marked inhibition of transformation that is rescued by suppression of endogenous caspase-8. These observations thus identify an IB-independent apoptotic activity of NF-B2 p100 and help explain its unique tumour suppressor role.
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B2 p100 is a pro-apoptotic protein with anti-oncogenic function
B (NF-
